Functional Food Nutrients, Redox Resilience Signaling and Neurosteroids for Brain Health

Abstract

The interplay between functional food nutrients and neurosteroids has garnered significant attention for its potential to enhance stress resilience in health and/or disease. Several bioactive nutrients, including medicinal herbs, flavonoids, and bioavailable polyphenol-combined nanoparticles, as well as probiotics, vitamin D and omega-3 fatty acids, have been shown to improve blood-brain barrier (BBB) dysfunction, endogenous neurosteroid homeostasis and brain function. These nutrients can inhibit oxidative stress and neuroinflammation, which are linked to the pathogenesis of various neurological disorders. Interestingly, flavonoids exhibit dose-dependent effects, activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway at the physiological/low dose (neurohormesis). This leads to the upregulation of antioxidant phase II genes and proteins such as heme oxygenase-1 (HO-1) and sirtuin-1 (Sirt1), which are activated by curcumin and resveratrol, respectively. These adaptive neuronal response mechanisms help protect against reactive oxygen species (ROS) and neurotoxicity. Impaired Nrf2 and neurosteroid hormone signaling in the brain can exacerbate selective vulnerability to neuroinflammatory conditions, contributing to the onset and progression of neurodegenerative and psychiatric disorders, including Alzheimer's disease, anxiety and depression and other neurological disorders, due to the vulnerability of neurons to stress. This review focuses on functional food nutrients targeting Nrf2 antioxidant pathway and redox resilience genes to regulate the neurosteroid homeostasis and BBB damage associated with altered GABAergic neurotransmission. By exploring the underlying molecular mechanisms using innovative technologies, we aim to develop promising neuroprotective strategies and personalized nutritional and neuroregenerative therapies to prevent or attenuate oxidative stress and neuroinflammation, ultimately promoting brain health.

Keywords: GABA signaling; Nrf2 pathway; central nervous system disorders; cerebral organoids; functional food nutrients; neurohormesis; neuroinflammation; neurosteroids; oxidative stress; polyphenols.

Figure 1

Neurohormetic nutrients and neurosteroids promote brain health through the activation of Nrf2 pathway and GABARs. Neurohormetic nutrients, including polyphenols (resveratrol, Hidrox^®, sulforaphane, curcumin and 3-epigallocatechin gallate) but also probiotics and ω3 fatty acids (EPA and DHA), protect neurons against oxidative injury and neuroinflammation in a dose-dependent manner. Interestingly, moderate/low doses of food nutrients can modulate the antioxidant pathway and stress resilience genes and proteins, particularly, Hsp70 and HO-1, γ-GCs, Sirt1 and FOXO3, which efficiently remove ROS and provide neuroprotection during CNS disorders. In addition, functional nutrients induce brain health by upregulating GABA via GABARs activation. Likewise, neurosteroids such as vitamin D, 17β-estradiol, DHEA, DHEAS, progesterone and particularly allopregnanolone are potent neuromodulators of GABA through GABARs. The activation of GABARs inhibits neuroinflammatory cytokine cascade and microglia activation, thereby preventing BBB dysfunction and the onset and progression of neurodegenerative and psychiatric disorders. We hypothesize that the synergistic action of neurohormetic nutrients and neurosteroids could potentiate their neuroprotective and neuroregenerative effects through a potential crosstalk between the Nrf2 pathway and GABAergic signaling via GABARs for the prevention and therapy of CNS disorders, ultimately promoting brain health and longevity in humans.

Figure 2

Potential molecular pathways ↑ upregulated or ↓ downregulated by neurosteroids in nervous system disorders in a dose-dependent manner (Neurohormesis).

Figure 3

Overview of the potential crosstalk between Nrf2 pathway and GABAergic signaling activated by functional nutrients and neurosteroids through GABARs for neuroprotection and neuro-regenerative therapy via neurohormetic dose–response effects. GAD: glutamic acid decarboxylase. ↑ upregulated and ↓ downregulated.